Leber's hereditary optic neuropathy (LHON) is a maternally-inherited form of acute, severe visual loss that affects otherwise healthy young people. LHON is the first human disease conclusively linked to an inherited mutation in mitochondrial DNA (mtDNA). The pathogenesis of visual loss in LHON appears to involve a complex interplay of genetic factors (primary and secondary mtDNA mutations) and epigenetic factors (most notably tobacco and alcohol use) that selectively affect the optic nerve. We hypothesize that the central pathogenetic feature of LHON is the net overall impairment of oxidative phosphorylation, which is induced by primary mtDNA mutations acting in concert with secondary mtDNA mutations and environmental factors. Genetic factors may predominate in some forms of acute optic neuropathy, while in others the epigenetic risk factor exposure is more prominent. The diversity of genetic factors (mtDNA mutations that occur in genes that are subunits of different complexes of oxidative phosphorylation) and epigenetic factors that can adversely affect oxidative phosphorylation may be reflected in distinctive phenotypic effects. To test these hypotheses, we propose studies with the following specific aims: 1. To define the pathogenetic role of secondary mtDNA mutations by determining their prevalence in groups of LHON probands that harbor each known primary mtDNA mutation and by using them to predict the coexistence of new primary mtDNA mutations in LHON probands. 2. To compare the mtDNA mutations associated with LHON to those associated with tobacco-alcohol amblyopia. Pathogenetic mtDNA mutations should occur in mtDNA-encoded subunits of all complexes of oxidative phosphorylation. MtDNA mutations might act as genetic susceptibility factors in tobacco-alcohol amblyopia and these patients should have an increased prevalence of known primary and secondary mtDNA mutations. A subset of patients with tobacco-alcohol amblyopia may represent a form fruste of LHON, while another subset may harbor unique mtDNA mutations. 3. To compare and contrast the genotype-specific clinical phenotypes associated with each primary mtDNA mutation to determine if the clinical phenotypes reflect the underlying molecular and biochemical heterogeneity. Conversely the specific features of the clinical phenotype may be predictive of the underlying mtDNA genotype. LHON may serve as a paradigm for mtDNA-mediated human diseases and for other diseases in which genetic and epigenetic factors pathogenetically interact.